Novel methods for synthesizing enantiopure (S)-methadone, (R)-methadone, racemic (R,S)-methadone, and related analogues.

Abstract

A method for the synthesis of enantiopure (S)-methadone, (R)-methadone, (R,S)-methadone, and related analogues with retention of stereochemical configuration starting from optically active or racemic N-substituted cyclic sulfamidates or N-substituted aziridines. The method avoids the formation of isomethadone-nitrile by-products observed under previously reported conditions, i.e., during the ring-opening reaction of the corresponding 1,1,2-trimethylaziridin-1-ium salts with 2,2-diphenylacetonitrile anion, thereby improving yields and facilitating purification procedures.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to and benefit of U.S. Patent Application No. 63 / 172,901, filed on April 9, 2021, the disclosure of which is incorporated herein by reference in whole.

[0002] The present invention generally relates to methods for the synthesis of enantiopurity (S)-methadone, (R)-methadone, (R,S)-methadone, and related analogues. [Background technology]

[0003] This section is intended to introduce to the reader various aspects of the art that may relate to the various aspects of the invention described and / or claimed below. This description is intended to be useful in providing the reader with background information to facilitate an understanding of the various aspects of the invention. Therefore, it should be understood that these descriptions should be read in this context and not as an endorsement of prior art.

[0004] As initially discovered by the present applicants, (S)-methadone (sometimes referred to herein as dextromethadone, esmethadone, and / or REL-1017), a dextrorotatory isomer of methadone, is a non-competitive, low-affinity, low-potency N-methyl-D-aspartate (NMDA) receptor antagonist that exhibits directionality to pathologically and persistently open hyperactive ion channels, and therefore exerts potential efficacy against numerous diseases and disorders at well-tolerated doses without psychotropic effects (Gorman AL, Elliott KJ, Inturrisi CE. The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett. 1997 Feb 14;223(1):5-8). doi:10.1016 / s0304-3940(97)13391-2. PMID:9058409;Bernstein G, Davis K, Mills C, Wang L, McDonnell M, Oldenhof J, Inturrisi C, Manfredi PL, Vitolo OV. Characterization of the Safety and Pharmacokinetic Profile of D-Methadone, a Novel N-Methyl-D-Aspartate Receptor Antagonist in Healthy, Opioid-Naive Subjects:Results of TWOPhase 1 Studies. J Clin Psychopharmacol. 2019 May / Jun;39(3):226-237. doi:10.1097 / JCP.0000000000001035.PMID:30939592;Fava M, Stahl S, Pani L, De Martin S, Pappagallo M, Guidetti C, Alimonti A, Bettini E, Mangano RM, Wessel T, de Somer M, Caron J, Vitolo OV, DiGuglielmo GR, Gilbert A, Mehta H, Kearney M, Mattarei A, Gentilucci M, Folli F, Traversa S, Inturrisi CE, Manfredi PL. REL-1017 (Esmethadone)as Adjunctive Treatment in Patients With Major Depressive Disorder:A Phase 2a Randomized Double-Blind Trial. Am J Psychiatry. 2022 Feb;179(2):122-131. doi:10.1176 / appi.ajp.2021.21020197. Epub 2021 (December 22. PMID:34933568). Esmethadone exhibits 20 times lower affinity for opioid receptors compared to its enantiomer (R)-methadone (Codd EE, Shank RP, Schupsky JJ, Raffa RB. Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther. 1995 Sep;274(3):1263-70. PMID:7562497), and does not show significant opioid agonist effects such as addiction tendencies.

[0005] Racemimemethadone is used to treat opioid use disorder (OUD) and pain. Based on clinical and experimental evidence, patients may be administered half the dose of (R)-methadone instead of (R,S)-methadone. (Gutwinski S, Schoofs N, Stuke H, Riemer TG, Wiers CE, Bermpohl F. Opioid tolerance in methadone maintenance treatment: comparison of methadone and levomethadone in long-term treatment. Harm Reduct J. 2016 Feb 16;13:7. doi:10.1186 / s12954-016-0095-0. PMID:26879120;PMCID:PMC4754801; Soyka M, Zingg C. Feasibility and safety of transfer from racemic methadone to (R)-methadone in primary care: clinical results from an open study. World J Biol Psychiatry.) 2009;10(3):217-24. doi:10.1080 / 15622970802416057. PMID:19629858). Administration of the (R) form would 2-fold decrease in plasma concentrations of methadone, thereby making the safety profile safer without affecting activity to μ-opioid receptors. In addition, the prescription of (R)-methadone would reduce clinical concerns due to delayed metabolism of CYP2B6 for cardiotoxic effects.Therefore, (R)-methadone, at doses used to treat OUD and pain, can reduce the risk of QTc interval prolongation (the time from the start of the Q wave to the end of the T wave, the time required for ventricular depolarization and repolarization), thereby improving the safety profile compared to (R,S)-methadone (Grilo LS, Carrupt PA, Abriel H. Stereoselective Inhibition of the hERG1 Potassium Channel. Front Pharmacol. 2010 Nov 22;1:137. doi:10.3389 / fphar.2010.00137. PMID:21833176;PMCID:PMC3153011).

[0006] The apparent importance of these two methadone isomers, and the advantages of administering them as separate drugs (rather than racemic methadone), clearly demonstrate the importance of developing cost-effective procedures for the synthesis of methadone isomers with high optical purity.

[0007] In 1957, Beckett et al. reported the first protocol for the stereoselective synthesis of (R)-methadone starting from (R)-alanine [Beckett, AH, and NJ Harper. "162. Configurational studies in synthetic analgesics: the synthesis of (-)-methadone from D-(-)-alanine." Journal of the Chemical Society (Resumed)(1957):858-861]. This protocol involved seven steps, yielding the final levomethadone with an overall yield of approximately 5% and an optical purity of approximately 72%. In principle, this procedure can be used for the preparation of both (R)-methadone and (S)-methadone. However, due to the complexity of the synthetic route, low optical purity, and low overall yield, it is not practical and its use is abandoned, especially in the pharmaceutical industry.

[0008] In 2000, Scheinmann et al., U.S. Patent No. 6,143,933, provided a method encompassing the enzymatic resolution of the racemic intermediate 1-(dimethylamino)propan-2-ol, followed by the conversion of the enantiomers to optically active (R)- and (S)-methadones with an overall yield of approximately 3% and an enantiomer excess of over 99%. Despite the excellent enantiomer excess achieved, the overall yield of this method is extremely low, and the inclusion of the enzymatic reaction is not practical and is considered to impose a high cost burden on industrial-scale processes. Furthermore, methods based on the racemic synthesis of methadone and subsequent enantiomer resolution (including the method disclosed in U.S. Patent Application Publication No. 2014 / 0350302) suffer from the introduction of undesirable impurities, complex operations, and a significant reduction in the overall yield of the desired enantiomers, making them unattractive strategies for large-scale production.

[0009] U.S. Patent Application Publication No. 2017 / 0057909 by Mkrtchyan et al. represents a recent technological advance in the chiral synthesis of (R)- or (S)-methadones and provides a more efficient method for the synthesis of optically active methadones starting from (R)- or (S)-alanine, respectively, with an overall yield of approximately 20% and an enantiomer excess of over 99%. The most successful enantioselective procedure for the synthesis of optically pure methadone, provided by Mkrtchyan et al., consists of: converting (R)- or (S)-alanine to the corresponding enantiopure N,N-dimethyl-alanine; reducing N,N-dimethyl-alanine to form N,N-dimethyl-alaninol; converting N,N-dimethyl-alaninol to the corresponding chloride intermediate by substitution; mixing the chloride intermediate with a base to form 1,1,2-trimethylaziridine-1-ium in situ, followed by treatment with 2,2-diphenylacetonitrile to obtain enantiopure methadone-nitrile; and finally exposing the methadone-nitrile to ethylmagnesium bromide to form an ethylimine intermediate, which is then hydrolyzed in the presence of hydrochloric acid to obtain optically pure methadone hydrochloride (see Figure 1 illustrating this synthetic strategy for (S)-methadone).

[0010] When seeking the best results between these two enantiomers in the examples shown in Mkrtchyan's U.S. Patent Application Publication No. 2017 / 0057909 using this synthesis strategy, the selected reagents and conditions (and resulting yields) are: i) CH2O, Pd / C, H2, water, 20 hours at 50°C, then 1 hour at reflux (85% yield); ii) LiAlH4, THF, 0°C to reflux, 16 hours (68% yield); iii) SOCl2, CHCl3, 0°C to reflux, 1 hour (93% yield); iv) KOtBu, Ph2CHCN, DMF, 2.5 hours at room temperature, then 15 hours at 45°C (38% yield); v) EtMgBr, toluene, 3 hours at 110°C, then 6M HCl, 3 hours at 75°C (88% yield). Total yield: 18%

[0011] All synthesis procedures disclosed in the literature (e.g., WO2013 / 168000, WO2017 / 35224, WO2013 / 77720, and U.S. Patent Application Publication No. 2015 / 152081) involve one main step, shown as step "iv" in Figure 1, namely the intramolecular S of (generally) 1-dimethylamino-2-chloropropane under basic conditions. N The reaction is based on the attack of the 2,2-diphenylacetonitrile anion on 1,1,2-trimethylaziridin-1-ium produced by the two reactions. The diphenylacetonitrile anion can then attack the aziridinium salt from two sides, resulting in a competitive ring-opening reaction with low regiochemical distinction. When the attack occurs at the least substituted carbon atom of the aziridinium salt, the desired methadone-nitrile is formed. However, when the attack occurs at a higher carbon atom, the byproduct isomethadone-nitrile is formed (see Figure 2). Under optimal combinations of base, solvent, and reaction conditions, the result of this reaction is at best a 1:3 (isomethadone-nitrile:methadone-nitrile) mixture of the two regioisomer products. When the resulting mixture is then purified using a complex crystallization process that utilizes the more soluble isomethadone-nitrile, the recovery of the desired methadone-nitrile becomes inefficient, resulting in a low purification yield. [Prior art documents] [Patent Documents]

[0012] [Patent Document 1] U.S. Patent No. 6,143,933 [Patent Document 2] U.S. Patent Application Publication No. 2014 / 0350302 [Patent Document 3] U.S. Patent Application Publication No. 2017 / 0057909 [Patent Document 4] WO2013 / 168000 [Patent Document 5] WO2017 / 35224 [Patent Document 6] WO2013 / 77720 [Patent Document 7] U.S. Patent Application Publication No. 2015 / 152081 [Patent Document 8] U.S. Patent Application Publication No. 2020 / 0277250 A1 [Patent Document 9] WO2017 / 035225 A1 [Patent Document 10] U.S. Patent Application Publication No. 2000 / 6143933 [Patent Document 11] U.S. Patent Application Publication No. 2018 / 10040752 B2 [Patent Document 12] WO1997 / 45551A1 [Patent Document 13] IN2014 / MU04118 A [Patent Document 14] U.S. Patent Application Publication No. 2015 / 9212128 B2 [Patent Document 15] WO2012 / 014109 [Patent Document 16] WO2019 / 52545 [Patent Document 17] WO2014 / 159224 [Non-patent literature]

[0013]

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[0014] Specific exemplary embodiments of the present invention are described below. It should be understood that these embodiments are presented solely to the reader to provide a brief overview of the specific forms the invention may take, and that they are not intended to limit the scope of the invention. In fact, the invention may encompass various embodiments not expressly described below.

[0015] As described above, the apparent importance of these two methadone isomers, and the advantages of administering them as separate drugs, clearly demonstrate the importance of developing cost-effective procedures for the synthesis of methadone isomers with high optical purity. Accordingly, one aspect of the present invention relates to a novel enantioselective approach for the synthesis of (S)-methadone, (R)-methadone, (R,S)-methadone, and their analogues. In particular, one aspect includes a method for preparing (S)-methadone, (R)-methadone, or (R,S)-methadone from optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine. In certain embodiments, the method comprises a ring-opening reaction of an optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine with 2,2-diphenylacetonitrile in the presence of a base to obtain ((S)- or (R)-) or racemic N-protected dinormethadone nitrile with preservation of its stereochemistry. This ring-opening reaction is followed by a two-step / one-pot deprotection / reductive amination of the N-protected dinormethadone nitrile to obtain (R)-, (S)-, or (R,S)-methadone nitrile. Next, the (R)-, (S)-, or (R,S)-methadone nitrile is reacted with an organomagnesium halide reagent to form an ethyl-imine intermediate, followed by imine hydrolysis to obtain (R)-, (S)-, or (R,S)-methadone.

[0016] Another aspect of the present invention relates to a method for preparing (S)-methadone hydrochloride, (R)-methadone hydrochloride, or (R,S)-methadone hydrochloride from optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine. In certain embodiments, the method comprises a ring-opening reaction of optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine with diphenylacetonitrile in the presence of a base to obtain ((S)- or (R)-) or racemic N-protected dinormethadone nitrile with preservation of stereochemistry. This ring-opening reaction is followed by a two-step / one-pot deprotection / reductive amination of the N-protected dinormethadone nitrile to obtain (R)-, (S)-, or (R,S)-methadone nitrile. The reaction of (R)-, (S)-, or (R,S)-methadone nitrile with an organomagnesium halide reagent is carried out to form an ethyl-imine intermediate, followed by hydrochloric acid-mediated imine hydrolysis to obtain (R)-, (S)-, or (R,S)-methadone hydrochloride.

[0017] Another aspect of the present invention relates to compounds (or pharmaceutically acceptable salts thereof) prepared by the methods of the two embodiments described above. In various embodiments, the compound (or pharmaceutically acceptable salt thereof) has the following formula:

[0018] [ka]

[0019] In the formula, (1)R1~R 10Each occurrence is independently hydrogen, deuterium, halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate group, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate group; (2)R 11 and R 12 Each instance is independently hydrogen, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate groups; or R 11 and R 12 Each instance is independently selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, and nitrate groups; (3)NR 13 R 14is optionally substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate group, C3-C 12 cycloalkyl, or may be cyclized through heterocyclyl; (4) NR 13 R 14 when not cyclized, R 13 and R 14 are each independently, for each occurrence, hydrogen, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, optionally substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate group, or R 13 and R 14 are each independently, for each occurrence, selected from the group consisting of alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate group; (5) Y is cyano, -C(O)R 15 、-C(OH)R 15 、-C(OR 16 )R 15 where R 15 and R 16Each instance is independently hydrogen, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate groups; or R 15 and R 16 Each instance of is independently selected from the group consisting of alkyl esters, alkoxys, carboxys, formyls, aryloxys, aminos, alkylaminos, arylamides, alkylamides, thiols, thioalkyls, thioaryls, alkylsulfonyls, alkylcarbamoyls, arylcarbamoyls, nitros, cyanos, and nitrate groups; (6)* is a stereocenter selected from (R)-, (S)-, or (R,S)- configurations, where the stereocenter is the R configuration and the compound exists with an enantiomer excess (ee) of 90%, 95%, 97%, 99%, 99.5%, or 99.9% compared to the S isomer, or the stereocenter is the S configuration and the compound exists with an enantiomer excess (ee) of 90%, 95%, 97%, 99%, 99.5%, or 99.9% compared to the R isomer.

[0020] A further aspect of the present invention relates to a method for the chromatography-free and scalable preparation of cyclic sulfamide date starting materials selected from benzyl(S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide, (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide, and (R,S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide.

[0021] A further aspect of the present invention relates to a method for preparing (R)-, (S)-, or (R,S)-methadone nitriles. In this aspect, the method includes a ring-opening reaction of an optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine with diphenylacetonitrile in the presence of a base to obtain ((S)- or (R)-) or racemic N-protected dinormethadone nitrile with preservation of its stereochemistry. This step is followed by a two-step / one-pot deprotection / reductive amination of the N-protected dinormethadone nitrile to obtain (R)-, (S)-, or (R,S)-methadone nitrile.

[0022] Another aspect of the present invention relates to a ring-opening reaction of an optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine with diphenylacetonitrile in the presence of a base, for obtaining an ((S)- or (R)-) or racemic N-protected dinormethadonenitrile with preservation of its stereochemistry.

[0023] The accompanying drawings incorporated herein and constituting part thereof illustrate embodiments of the present invention and, together with the general description of the present invention set forth above and the detailed description of embodiments set forth below, serve to illustrate the principles of the present invention. [Brief explanation of the drawing]

[0024] [Figure 1] This is a schematic diagram illustrating the synthesis of (S)-methadone using the strategy proposed in U.S. Patent Application Publication No. 2017 / 0057909. [Figure 2] This is a schematic diagram showing the main steps in a previously reported procedure for the synthesis of (R)-, (S)-, and (R,S)-methadones. [Figure 3] This is a schematic diagram of the procedure for preparing (R)-, (S)-, or (R,S)-methadone. [Figure 4] This is a schematic diagram of the procedure for preparing N-protected cyclic sulfamide starting material. [Figure 5]This is a schematic diagram of the preparation of N-protected 2-methylaziridine starting materials. [Figure 6] The general structures of enantiopure or racemic methadone analogs that can be synthesized using the methods disclosed herein are shown. [Figure 7] This is a schematic diagram illustrating the synthesis of Cbz-protected (S)-cyclic sulfamide starting materials. [Figure 8] This graph shows the 1H NMR spectrum of benzyl(S)-(1-hydroxypropan-2-yl)carbamate. [Figure 9] This graph shows the 1H NMR spectrum of benzyl(S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide. [Figure 10] This graph shows the 13C NMR spectrum of benzyl(S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide. [Figure 11] This is a schematic diagram illustrating the synthesis of Boc-protected(R)-aziridine starting materials. [Figure 12] This graph shows the 1H NMR spectrum of tert-butyl(R)-(1-hydroxypropan-2-yl)carbamate. [Figure 13] This graph shows the 13C NMR spectrum of tert-butyl(R)-(1-hydroxypropan-2-yl)carbamate. [Figure 14] This graph shows the 1H NMR spectrum of tert-butyl(R)-2-methylaziridine-1-carboxylate. [Figure 15] This graph shows the 13C NMR spectrum of tert-butyl(R)-2-methylaziridine-1-carboxylate. [Figure 16] This is a schematic diagram illustrating the synthesis of (S)-methadone nitrile using Cbz-protected (S)-cyclic sulfamide date as a starting material. [Figure 17] This graph shows the 1H NMR spectrum of benzyl(S)-(4-cyano-4,4-diphenylbutan-2-yl)carbamate. [Figure 18] This graph shows the 13C NMR spectrum of benzyl(S)-(4-cyano-4,4-diphenylbutan-2-yl)carbamate. [Figure 19A] These are graphs and tables showing the chiral HPLC chromatograms of (R,S)-methadone nitrile. [Figure 19B] This is a graph and table showing the chiral HPLC chromatogram of (S)-methadone nitrile. [Figure 20] This graph shows the 1H NMR spectrum of (S)-methadone nitrile. [Figure 21] This graph shows the 13C NMR spectrum of (S)-methadone nitrile. [Figure 22] This is a schematic diagram illustrating the synthesis of (R)-methadone nitrile using Boc-protected (R)-2-methylaziridine starting material. [Figure 23] This graph shows the 1H NMR spectrum of tert-butyl(R)-(4-cyano-4,4-diphenylbutan-2-yl)carbamate. [Figure 24] This graph shows the 13C NMR spectrum of tert-butyl(R)-(4-cyano-4,4-diphenylbutan-2-yl)carbamate. [Figure 25A] This is a chiral HPLC chromatogram of (R,S)-methadone nitrile. [Figure 25B] This is the chiral HPLC chromatogram of (R)-methadone nitrile. [Figure 26] This graph shows the 1H NMR spectrum of (R)-methadone nitrile. [Figure 27] This graph shows the 13C NMR spectrum of (R)-methadone nitrile. [Figure 28] This is a schematic diagram illustrating the synthesis of (S)-methadone hydrochloride from (S)-4-(dimethylamino)-2,2-diphenylpentannitrile. [Figure 29A] This is the chiral HPLC chromatogram of (R,S)-methadone. [Figure 29B] This is the chiral HPLC chromatogram of (S)-methadone. [Figure 30] This graph shows the 1H NMR spectrum of (S)-methadone*HCl. [Figure 31] This graph shows the 13C NMR spectrum of (S)-methadone*HCl. [Figure 32] This is a schematic diagram illustrating the synthesis of (R)-methadone hydrochloride from (R)-4-(dimethylamino)-2,2-diphenylpentannitrile. [Figure 33A] This is the chiral HPLC chromatogram of (R,S)-methadone. [Figure 33B] This is the chiral HPLC chromatogram of (R)-methadone. [Figure 34] This graph shows the 1H NMR spectrum of (R)-methadone*HCl. [Figure 35] This graph shows the 13C NMR spectrum of (R)-methadone*HCl. [Modes for carrying out the invention]

[0025] One or more specific embodiments of the present invention are described below. In order to provide a concise description of these embodiments, not all features of the actual embodiments may be described herein. It should be recognized that in developing any such actual embodiment, as in any engineering or design project, a number of embodiment-specific decisions must be made to achieve the specific goals of the developers, which may differ from embodiment to embodiment, such as compliance with system-related and business-related constraints. Furthermore, it should be recognized that such development attempts, while complex and time-consuming, will nevertheless be routine design, fabrication, and manufacturing work for those skilled in the art who benefit from the present disclosure.

[0026] As described above, one aspect of the present invention relates to a method for preparing (S)-methadone, (R)-methadone, or (R,S)-methadone from optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine. In certain embodiments, the method comprises a ring-opening reaction of optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine with 2,2-diphenylacetonitrile in the presence of a base to obtain ((S)- or (R)-) or racemic N-protected dinormethadone nitrile with preservation of stereochemistry. This ring-opening reaction is followed by a two-step / one-pot deprotection / reductive amination of the N-protected dinormethadone nitrile to obtain (R)-, (S)-, or (R,S)-methadone nitrile. Next, a reaction is carried out between (R)-, (S)-, or (R,S)-methadone nitrile and an organomagnesium halide reagent to form an ethyl-imine intermediate, followed by imine hydrolysis to obtain (R)-, (S)-, or (R,S)-methadone.

[0027] Another aspect of the present invention relates to a method for preparing (S)-methadone hydrochloride, (R)-methadone hydrochloride, or (R,S)-methadone hydrochloride from optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine. In certain embodiments, the method comprises a ring-opening reaction of optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine with diphenylacetonitrile in the presence of a base to obtain ((S)- or (R)-) or racemic N-protected dinormethadone nitrile with preservation of stereochemistry. This ring-opening reaction is followed by a two-step / one-pot deprotection / reductive amination of the N-protected dinormethadone nitrile to obtain (R)-, (S)-, or (R,S)-methadone nitrile. The reaction of (R)-, (S)-, or (R,S)-methadone nitrile with an organomagnesium halide reagent is carried out to form an ethyl-imine intermediate, followed by hydrochloric acid-mediated imine hydrolysis to obtain (R)-, (S)-, or (R,S)-methadone hydrochloride.

[0028] Another aspect of the present invention relates to compounds (or pharmaceutically acceptable salts thereof) prepared by the methods of the two embodiments described above. In various embodiments, the compound (or pharmaceutically acceptable salt thereof) has the following formula:

[0029] [ka]

[0030] In the formula, (1)R1~R 10Each occurrence is independently hydrogen, deuterium, halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate group, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate group; (2)R 11 and R 12 Each instance is independently hydrogen, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate groups; or R 11 and R 12 Each instance is independently selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, and nitrate groups; (3)NR 13 R 14Each of these C3-C3 groups may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate groups. 12 (4)NR 13 R 14 If R is not cyclized, 13 and R 14 Each instance is independently hydrogen, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate groups, or R 13 and R 14 Each instance is independently selected from the group consisting of alkyl esters, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, and nitrate groups; (5)Y is cyano, -C(O)R 15 -C(OH)R 15 , -C(OR 16 )R 15 And R 15 and R 16Each instance is independently hydrogen, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate groups; or R 15 and R 16 Each instance of is independently selected from the group consisting of alkyl esters, alkoxys, carboxys, formyls, aryloxys, aminos, alkylaminos, arylamides, alkylamides, thiols, thioalkyls, thioaryls, alkylsulfonyls, alkylcarbamoyls, arylcarbamoyls, nitros, cyanos, and nitrate groups; (6)* is a stereocenter selected from (R)-, (S)-, or (R,S)- configurations, where the stereocenter is the R configuration and the compound exists with an enantiomer excess (ee) of 90%, 95%, 97%, 99%, 99.5%, or 99.9% compared to the S isomer, or the stereocenter is the S configuration and the compound exists with an enantiomer excess (ee) of 90%, 95%, 97%, 99%, 99.5%, or 99.9% compared to the R isomer.

[0031] A further aspect of the present invention relates to a method for the chromatography-free and scalable preparation of cyclic sulfamide date starting materials selected from benzyl(S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide, (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide, and (R,S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide.

[0032] A further aspect of the present invention relates to a method for preparing (R)-, (S)-, or (R,S)-methadone nitriles. In this aspect, the method includes a ring-opening reaction of an optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine with diphenylacetonitrile in the presence of a base to obtain ((S)- or (R)-) or racemic N-protected dinormethadone nitrile with preservation of its stereochemistry. This step is followed by a two-step / one-pot deprotection / reductive amination of the N-protected dinormethadone nitrile to obtain (R)-, (S)-, or (R,S)-methadone nitrile.

[0033] Another aspect of the present invention relates to a ring-opening reaction of an optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine with diphenylacetonitrile in the presence of a base, for obtaining an ((S)- or (R)-) or racemic N-protected dinormesadonenitrile with preservation of its stereochemistry.

[0034] The methods disclosed herein for the synthesis of (S)-methadone, (R)-methadone, (R,S)-methadone, and their analogues are enantioretaining and scalable three-step methods ending with the isolation of (R), (S), or (R,S)-methadone in hydrochloride form, and were conceived and developed by the inventors. Referring to Figure 3, a key feature of these methods is the strategic use of a chiral pool, using N-protected cyclic 4-methyl-sulfamidate (1) or N-protected 2-methylaziridine (2) derived from (R), (S), or (R,S)-alaninol as the main starting material for the synthesis. The N protecting group can be selected from among the most common carbamate protecting groups for amines [e.g., fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), carboxybenzyl (Cbz), acetyl (C(O)CH3), trifluoroacetyl (C(O)CF3), benzyl (Bn), triphenylmethyl (CPh3), p-toluenesulfonyl (Ts)].

[0035] Previously reported methods for the synthesis of (R)- and (S)-methadone consist of nucleophilic ring-opening reactions of aziridinium. However, these techniques suffer from low regioselectivity, which leads to isomeric impurities that make the purification and isolation of the desired nitrile intermediate difficult (see, for example, the methods disclosed in U.S. Patent Application Publication 2020 / 0277250 A1; WO, 2017 / 035225 A1; WO2017 / 035524 A1; U.S. Patent Application Publication 2000 / 6143933; and U.S. Patent Application Publication 2018 / 10040752 B2). Furthermore, unlike ring-opening of N-protected cyclic 4-methyl-sulfamidate (1) or N-protected 2-methylaziridine (2), the aziridinium strategy can result in loss of optical purity, thus requiring decomposition techniques for the isolation of enantiopure materials (as described in WO2013 / 077720 A1; WO1997 / 45551 A1; IN2014 / MU04118 A; U.S. Patent Application Publication No. 2015 / 9212128 B2).

[0036] In the methods of the present disclosure relating to aspects of the present invention, and further referring to Figure 3, step 1 of the method was useful in minimizing positional isomer byproducts (i.e., isomethadone-nitrile) observed in previous synthesis. By using N-protected cyclic 4-methyl-sulfamidate (1) as a starting material for the reaction with 2,2-diphenylacetonitrile (3) in the presence of a base, an N-protected intermediate (4) was obtained after crystallization in good yield and purity. Similarly, the reaction of N-protected 2-methylaziridine (2) with 2,2-diphenylacetonitrile (3) in the presence of a base was converted to an N-protected intermediate (4) after purification in good yield and efficiency.

[0037] Step 2 of this method (as described above) is a two-step / one-pot deprotection / reductive amination of the N-protected intermediate (4), thereby synthesizing the common intermediates (R)-, (S)-, or (R,S)-methadone nitrile (5) in good yield and purity. As shown in the examples below, the reaction conditions for step 2 depend on the N-protecting group employed.

[0038] In step 3 of this method (as described above), as already disclosed, the intermediate (R)-, (S)-, or (R,S)-methadone nitrile (5) was treated with a slightly excess amount of EtMgBr (an example of an organomagnesium halide agent) to produce the corresponding ethyl-imine, which was hydrolyzed under acidic conditions to obtain (R)-, (S)-, or (R,S)-methadone. The desired (R)-, (S)-, or (R,S)-methadone was isolated in good yield and high purity by seed crystallization.

[0039] Referring here to Figure 4, an N-protected cyclic 4-methyl sulfamidate (one possible starting material) can be produced in a two-step method starting from (R)-, (S)-, or (R,S)-2-aminopropan-1-ol (1.1). The first step is the protection of the amino group with a selected protecting group to obtain the corresponding N-protected (R)-, (S)-, or (R,S)-2-aminopropan-1-ol (1.2). The second step is a two-step / one-pot process to obtain an N-protected cyclic sulfamidite intermediate (1.3 in step 2a) by first cyclization with thionyl chloride in the presence of a base, and then the desired N-protected cyclic sulfamidate (1) in good yield and purity after crystallization by oxidation of the sulfur atom in the presence of sodium periodate as an oxidizing agent and ruthenium chloride as a catalyst (step 2b) (see Figure 4).

[0040] N-protected 2-methylaziridine (alternative starting material) can be produced by a two-step method already disclosed, for example, in WO2012 / 014109 or WO2019 / 52545, starting from (R)-, (S)-, or (R,S)-2-aminopropan-1-ol (1.1). Referring to Figure 5, the first step in this production is the protection of the amino group with a selected carbamate protecting group to obtain the corresponding N-protected (R)-, (S)-, or (R,S)-2-aminopropan-1-ol (1.2). The second step is a two-step / one-pot process to obtain the desired N-protected 2-methylaziridine (2) in good yield and purity by first reacting it with p-toluenesulfonyl chloride in the presence of a base to obtain an N-protected (R)-, (S)-, or (R,S)-2-aminopropane-1-tosylate intermediate (2.1 in step 2a), and then by aziridine cyclization (step 2b).

[0041] As mentioned above, the method disclosed herein is also applicable to the synthesis of methadone analogs relating to general formula (I) shown below and in Figure 6:

[0042] [ka]

[0043] [In the formula, R1~R 10Each occurrence is independently hydrogen, deuterium, halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate group, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate group; R 11 and R 12 Each instance is independently hydrogen, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate groups; or R 11 and R 12 Each instance is independently selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, and nitrate groups; NR 13 R 14Each of these C3-C3 groups may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate groups. 12 It may also be cyclized via a cycloalkyl or heterocyclyl group; NR 13 R 14 If R is not cyclized, 13 and R 14 Each instance is independently hydrogen, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate groups, or R 13 and R 14 Each instance is independently selected from the group consisting of alkyl esters, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, and nitrate groups; Y is cyano, -C(O)R 15 -C(OH)R 15 , -C(OR 16 )R 15 And R 15 and R 16Each instance is independently hydrogen, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate groups; or R 15 and R 16 Each occurrence is independently selected from the group consisting of alkyl esters, alkoxys, carboxys, formyls, aryloxys, aminos, alkylaminos, arylamides, alkylamides, thiols, thioalkyls, thioaryls, alkylsulfonyls, alkylcarbamoyls, arylcarbamoyls, nitros, cyanos, and nitrate groups; * is a stereocenter selected from (R)-, (S)-, or (R,S)- configurations, where the stereocenter is in the R configuration and the compound exists with an enantiomer excess (ee) of 90%, 95%, 97%, 99%, 99.5%, or 99.9% compared to the S isomer, or where the stereocenter is in the S configuration and the compound exists with an enantiomer excess (ee) of 90%, 95%, 97%, 99%, 99.5%, or 99.9% compared to the R isomer. [Examples]

[0044] The compound structures in the following examples were confirmed by one or more of the following methods: 1 1H NMR, 13 C NMR, mass spectrometry (LC-MS), FTIR spectroscopy, HPLC-UV, chiral-HPLC. 1The 1H NMR spectra were determined using an NMR spectrometer operating at a 300 MHz or 400 MHz magnetic field. The chemical shifts were based on signals from residual protons in the deuterated solvent as follows: CDCl3 = 7.25 ppm, DMSO-d6 = 2.49 ppm, CD3OD = 0.30 ppm. Peak multiplicity is expressed as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; dt, triplet of doublet; q, quadruplet; br, broad; m, multiplet. Coupling constants are shown in Hertz (Hz).

[0045] Mass spectral (MS) data is obtained using a mass spectrometer equipped with an ESI ion source, and an ion trap or TOF mass spectrometer.

[0046] In the following embodiments, unless otherwise specified, reagents and solvents may be purchased from commercial suppliers and used without further purification.

[0047] Example 1: Benzyl(S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide((S)-1') This Example 1 describes a two-step method, shown in Figure 7, used to prepare benzyl(S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide((S)-1').

[0048] Step 1: Cbz protection of (S)-2-aminopropan-1-ol ((S)-1.1) to form benzyl(S)-(1-hydroxypropan-2-yl)carbamate ((S)-1.2'). (S)-2-aminopropan-1-ol ((S)-1.1) (100.0 g, 1331 mmol, 1.0 equivalent), ethyl acetate (1000 mL, 10 volumes), and 7.5% (w / v) NaHCO3 (aqueous solution) (1000 mL, 10 volumes) were added to a 5 L round-bottom flask equipped with an overhead mechanical stirrer, thermocouple, N2 inlet, and addition funnel. The stirred solution was cooled to 0°C in an ice bath, and 209.0 mL, 1460 mmol, 1.1 equivalents of CbzCl were added over 25 minutes using the addition funnel. The two-phase reaction solution was equilibrated to an internal temperature of 20°C over 16 hours. 1 Upon completion of the reaction, as determined by the consumption of (S)-1.1 by 1H-NMR and TLC (DCM:MeOH [9:1 ratio], using cerium ammonium molybdate staining, Rf = approximately 0.6), stirring was discontinued and the two-phase mixture was settled. The organic fraction was separated, and the aqueous fraction was further extracted with IPAc (2 x 500 mL, 5 vol). The combined organic layers were washed with 36% (w / v) NaCl (aqueous solution) (100 mL, 1 vol) and evaporated under reduced pressure to obtain a colorless oil. The crude material was diluted with IPAc (2.8 vol, 280 mL) and heated to 45°C with rotary stirring. After 45 minutes, dissolution was not complete, so additional IPAc (2.8 vol, 280 mL) was added, and heating under stirring was continued. Dissolution was complete after 1 hour. Heating was discontinued, and standard ((S)-1.2') (approximately 100 mg) was seeded into the solution. A free-flowing slurry was obtained by moderate stirring (200-250 rpm) for 16 hours while equilibrating at 20°C. The solid was collected by vacuum filtration and dried under reduced pressure at 45°C to obtain benzyl(S)-(1-hydroxypropan-2-yl)carbamate ((S)-1.2') as a white solid (185.9 g, yield 67%) in a single collection. Further crystallization attempts were made by concentrating the mother liquor and then adding standard ((S)-1.2') as a seed to obtain a free-flowing slurry, which was then filtered and dried under reduced pressure to obtain an additional 21.4 g of benzyl(S)-(1-hydroxypropan-2-yl)carbamate ((S)-1.2') as a white solid. Total isolated amount after the second collection: 207.3 g, yield 74%. 1¹H NMR (400 MHz, acetonitrile-d3) δ values ​​were 7.41 - 7.28 (m, 5H), 5.51 (s, 1H), 5.10 - 5.01 (m, 2H), 3.72 - 3.59 (m, 1H), 3.47 - 3.35 (m, 2H), 2.89 (s, 1H), and 1.08 (d, J = 6.8 Hz, 3H), as shown in Figure 8.

[0049] Step 2: Two-step / one-pot crystallization / oxidation to form benzyl(S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide((S)-1'). Imidazole (32.54 g, 477.9 mmol, 4.0 equivalents), DCM (100 mL, 4 volumes), and NEt3 (37 mL, 262.8 mmol, 2.2 equivalents) were added to a 400 mL Easy Max reactor equipped with an overhead mechanical stirrer, thermocouple, and N2 inlet. The vessel was purged with N2 for 30 minutes and cooled to an internal temperature of -35°C. A solution of thionyl chloride (9.5 mL, 131.4 mmol, 1.1 equivalents) in DCM (50 mL, 2 volumes) was added to the stirred suspension over 2 hours using a syringe pump, and the mixture was stirred for a further 15 minutes. To the resulting suspension, a solution of benzyl(S)-(1-hydroxypropan-2-yl)carbamate((S)-1,2') (25.00 g, 119.5 mmol, 1.0 equivalent) in DCM (100 mL, 4 volumes) was added over 1 hour using a syringe pump. The reaction mixture was heated to -30°C and stirred for 15 hours. HPLC and 1 Upon completion of the reaction, as determined by the consumption of 2 by 1H NMR, the reaction mixture was heated to 0°C over 2 hours. The reaction mixture was washed with H2O (2 x 10 vols), and the organic fraction was concentrated under reduced pressure. The crude oil was reconstituted in MeCN (100 mL, 4 vols) and H2O (125 mL, 5 vols), and then cooled to 0°C. NaIO4 (28.11 g, 131.4 mmol, 1.1 equivalents), followed by RuCl3 (25 mg, 0.12 mmol, 0.001 equivalents), was added to the stirred solution, and the solution was stirred at 0°C for 3 hours. HPLC and 1Upon completion of the reaction, as determined by the consumption of the intermediate sulfamidite by 1H NMR, the reaction mixture was treated with pH=7 KH2PO4 / KOH buffer (aqueous solution) (250 mL, 10 vols) and PhMe (100 mL, 4 vols). MeCN was removed under reduced pressure, and the organic fraction and aqueous fraction were separated. The aqueous fraction (pH=7) was further extracted with IPAc (2 x 4 vols), and the combined organic layers were concentrated under reduced pressure to an estimated 50 mL (approximately 2 vols). The solution was heated to 45°C, and standard (S)-3-Cbz-4-methyl-1,2,3-oxathiazolidine 2,2-dioxide 3 was seeded in. n-heptane (250 mL, 10 vols) was added dropwise to the stirred suspension over 1 hour to obtain a white slurry. The suspension was cooled, stirred at 20°C for 1 hour, slowly cooled to -20°C for 2 hours, and then stirred for a further 15 hours. The slurry was filtered, and the solid was washed with n-heptane (4 volumes). The collected solid was dried under reduced pressure at 20°C to obtain benzyl(S)-3-Cbz-4-methyl-1,2,3-oxathiazolidine 2,2-dioxide((S)-1') as a white solid (27.17 g, yield 84%). 1 ¹H NMR (400 MHz, acetonitrile-d3) δ values ​​were 7.48 - 7.34 (m, 5H), 5.36 - 5.23 (m, 2H), 4.72 (dd, J = 9.4, 5.8 Hz, 1H), 4.56 - 4.45 (m, 1H), 4.35 (dd, J = 9.4, 2.3 Hz, 1H), 1.44 (d, J = 6.4 Hz, 3H), as shown in Figure 9. 13 ¹³C NMR (10¹ MHz, acetonitrile-d3) δ values: 150.70, 136.16, 129.65, 129.61, 129.13, 73.69, 69.91, 55.70, 18.41, as shown in Figure 10.

[0050] Example 2: tert-butyl(R)-2-methylaziridine-1-carboxylate((R)-2'') This Example 2 describes a two-step method, shown in Figure 11, used to prepare tert-butyl(R)-2-methylaziridine-1-carboxylate((R)-2'').

[0051] Step 1: Boc protection of (R)-2-aminopropan-1-ol ((R)-1.1) to form tert-butyl(R)-(1-hydroxypropan-2-yl)carbamate ((R)-2.2'') This process was carried out in accordance with the procedures of the literature (see WO2014 / 159224, which is incorporated herein by reference in its entirety), with some modifications.

[0052] (R)-2-aminopropan-1-ol ((R)-1.1) (10.0 g, 133.1 mmol, 1.0 equivalent) and anhydrous THF (100 mL) were added to a 250 mL round-bottom flask under an N2 atmosphere. The flask was cooled to 0°C, and a solution of Boc2O (30.52 g, 139.8 mmol, 1.05 equivalent) in anhydrous THF (40 mL) was added dropwise over 30 minutes. The reaction mixture was stirred at 0°C for a further 1 hour, and then the temperature was raised to 20°C over a further 16 hours. 1 Stirring was stopped when the reaction was complete, as confirmed by 1H-NMR and TLC (DCM:MeOH [9:1 ratio], potassium permanganate staining used, Rf = approximately 0.6) based on the consumption of (R)-1.1. The organic layer was concentrated under reduced pressure, and the residue was triturated with n-hexane. The resulting solid was filtered and air-dried to obtain the marked compound ((R)-2.2'') as a colorless solid (20.81 g, yield 89%). HRMS (ESI): m / z C8H 17 NO3+ Na + [M+Na] + Calculated value: 198.1101. Measured value: 198.0791. 1 ¹H NMR (300 MHz, CDCl3) δ 3.81 - 3.69 (m, 1H), 3.62 (dd, J = 10.9, 3.9 Hz, 1H), 3.49 (dd, J = 10.9, 6.1 Hz, 1H), 1.44 (s, 9H), 1.14 (d, J = 6.8 Hz, 3H) ppm, as shown in Figure 12. 13 ¹³C NMR (10¹ MHz, CDCl₃) δ values: 156.42, 79.69, 66.95, 48.63, 28.46, 17.40 ppm, as shown in Figure 13.

[0053] Step 2: Two-step / one-pot tosylation / cyclization to form tert-butyl(R)-2-methylaziridine-1-carboxylate((R)-2''). This process was carried out in accordance with the procedures described in the literature (see WO2012 / 14109, which is incorporated herein by reference in its entirety), with some modifications.

[0054] In a 250 mL round-bottom flask under an N2 atmosphere, tert-butyl(R)-(1-hydroxypropan-2-yl)carbamate((R)-2.2'') (10.00 g, 57.1 mmol, 1 equivalent), anhydrous diethyl ether (120 ml), and tosyl chloride (14.14 g, 74.2 mmol, 1.3 equivalents) were added. The reaction mixture was stirred for 15 minutes and then cooled to 0°C. Crushed potassium hydroxide (25.62 g, 456.8 mmol, 8 equivalents) was added in several portions over 30 minutes. The reaction mixture was heated to 45°C over approximately 3 hours. 1 Stirring was stopped when the reaction was complete, as determined by the consumption of (R)-2.2'' by 1H-NMR and TLC (Hex:SiO[8:2 ratio], potassium permanganate staining used, Rf=approx. 0.3). The reaction mixture was diluted with water (100 mL), the organic fraction was separated, and the aqueous fraction was further extracted with diethyl ether (2 x 50 mL). The combined organic layers were washed with 36% (w / v) NaCl (aqueous solution) (100 mL) and evaporated under reduced pressure to obtain tert-butyl(R)-2-methylaziridine-1-carboxylate((R)-2'') as a clear, colorless oil (7.04 g, yield 78%). 1 ¹H NMR (400 MHz, CDCl3) δ 2.48 - 2.39 (m, 1H), 2.23 (d, J = 5.8 Hz, 1H), 1.88 (d, J = 3.8 Hz, 1H), 1.45 (s, 9H), 1.27 (d, J = 5.5 Hz, 3H) ppm, as shown in Figure 14. 13 ¹³C NMR (10¹ MHz, CDCl₃) δ values: 162.61, 81.06, 33.71, 32.63, 28.08, 17.52 ppm, as shown in Figure 15.

[0055] Example 3: (S)-4-(dimethylamino)-2,2-diphenylpentanenitrile ((S)-5) This third example describes a two-step method, shown in Figure 16, used to prepare (S)-4-(dimethylamino)-2,2-diphenylpentanenitrile ((S)-5).

[0056] Step 1: Ring-opening reaction of benzyl(S)-4-methyl-1,2,3-oxathiazolidined-3-carboxylate 2,2-dioxide((S)-1') on a 2,2-diphenylacetonitrile(3) anion to form benzyl(S)-(4-cyano-4,4-diphenylbutan-2-yl)carbamate((S)-4'). Benzyl(S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide((S)-1') (10.00 g, 36.9 mmol, 1 equivalent) and diphenylacetonitrile(3) (7.85 g, 40.6 mmol, 1.1 equivalents) were added to a 400 mL Easy Max reactor equipped with an overhead mechanical stirrer, thermocouple, and N2 inlet. The vessel was purged with N2 for 30 minutes, diluted with 2-MeTHF (100 mL, 10 volumes), and cooled to an internal temperature of -20°C. NaHMDS (1 M THF solution, 44.3 mL, 44.3 mmol, 1.2 equivalents) was added dropwise to the stirred solution using a syringe pump over 1 hour, and the mixture was stirred for a further 15 hours. The mixture was heated to 0°C and stirred for 1 hour. Upon completion of the reaction, as determined by HPLC based on the consumption of (S)-1', the solution was treated by adding 5% (w / v) citric acid (aqueous solution) (50 mL, 5 vols) dropwise over 1 hour. The two-phase mixture was heated to 20°C to separate the organic and aqueous fractions. The aqueous fraction was further extracted with 2-MeTHF (2 x 50 mL, 5 vols). The combined organic layers were concentrated under reduced pressure at 35°C to an estimated 20 mL (approximately 2 vols). n-heptane (100 mL, 10 vols) was added dropwise to the stirred solution over 1 hour, followed by seeding with standard benzyl(S)-(4-cyano-4,4-diphenylbutan-2-yl)carbamate ((S)-4') to obtain a yellowish-white slurry. The slurry was stirred at 20°C for 6 hours, slowly cooled to -20°C for 15 hours (approximately 3°C / hour), and then stirred for another 15 hours. The slurry was filtered, and the solid was washed with n-heptane (3 x 10 vol). The collected solid was dried under reduced pressure at 20°C to obtain benzyl(S)-(4-cyano-4,4-diphenylbutan-2-yl)carbamate((S)-4') as a white solid (13.62 g, 96% yield). HPLC purity: 97.9%. HRMS (ESI) m / z: [M+H] + C 25 H 24 Calculated value of N2O2 385.19; measured value 385.20. 11H NMR (400 MHz, CDCl3) δ 7.51 - 7.20 (m, 15H), 5.06 (s, 2H), 4.99 (d, J = 8.3 Hz, 1H), 3.86 - 3.74 (m, 1H), 2.83 (dd, J = 14.4, 8.0 Hz, 1H), 2.48 (dd, J = 14.4, 4.7 Hz, 1H), 1.24 (d, J = 6.7 Hz, 3H) ppm, as shown in Figure 17. 13 13C NMR (400 MHz, CDCl3) δ 155.13, 139.96, 139.74, 136.57, 128.88, 128.82, 128.35, 127.93, 127.90, 126.84, 126.77, 122.31, 66.31, 49.25, 45.09, 44.89, 21.90 ppm, as shown in Figure 18.

[0057] Step 2: Two-step / one-pot deprotection / reductive amination of benzyl (S)-(4-cyano-4,4-diphenylbutan-2-yl) carbamate ((S)-4') to form (S)-mesadonnitrile ((S)-5) Benzyl(S)-(4-cyano-4,4-diphenylbutan-2-yl)carbamate ((S)-4') (1.00 g, 2.60 mmol, 1 equivalent) and Pd(OH)2 / C 20% supported activated carbon (460 mg, 0.65 mmol, 25 mol%) were added to a 100 mL Morton-type round-bottom flask equipped with a magnetic stirring bar. The container was purged with N2 for approximately 30 minutes, diluted with EtOH (20 mL, 20 vol), and then 37% w / w aqueous CH2O solution (2 mL, 2 vol) was added to the stirred solution. An H2 balloon was placed in the container, and the mixture was stirred at 25°C for 24 hours. Upon completion of the reaction, as determined by HPLC based on the consumption of ((S)-4'), the container was purged with N2 for approximately 30 minutes. The suspension was filtered through a Celite bed, eluted with EtOH (2 x 5 vol), and concentrated under reduced pressure to approximately 2 vol. H2O (14 mL, 14 vols) was added to a stirred ethanol solution over 1 hour, and the slurry was stirred at 25°C for 15 hours. It was cooled to approximately 5°C in an ice bath, and then stirred for a further 5 hours. The solid was collected by vacuum filtration and washed with H2O (5 mL, 5 vols). The collected solid was dried under reduced pressure at 50°C to obtain (S)-4-(dimethylamino)-2,2-diphenylpentanenitrile ((S)-5) as a white solid (630 mg, yield 87%). Chiral HPLC: one single enantiomer (ee>99%), as shown in Figure 19. HRMS (ESI) m / z: [M+H] + C 19 H 22 Calculated value for N2279.18; measured value for N279.20. 1 ¹H NMR (300 MHz, CDCl3) δ 7.49 - 7.22 (m, 10H), 2.69 (dd, J = 13.7, 6.4 Hz, 1H), 2.54 (h, J = 6.4 Hz, 1H), 2.23 (dd, J = 13.6, 6.0 Hz, 1H), 2.13 (s, 6H), 0.91 (d, J = 6.6 Hz, 3H). ppm, as shown in Figure 20. 13¹³C NMR (10¹ MHz, CDCl₃) δ values: 141.42, 140.80, 128.84, 128.76, 127.88, 127.73, 127.47, 127.30, 122.93, 55.54, 49.75, 43.42, 40.03, 13.16 ppm, as shown in Figure 21.

[0058] Example 4: (R)-4-(dimethylamino)-2,2-diphenylpentanenitrile ((R)-5) This Example 4 describes a two-step method, shown in Figure 22, used to prepare (R)-4-(dimethylamino)-2,2-diphenylpentanenitrile ((R)-5).

[0059] Step 1: Ring-opening reaction of tert-butyl(R)-2-methylaziridine-1-carboxylate((R)-2'') on a 2,2-diphenylacetonitrile(3) anion to form tert-butyl(R)-(4-cyano-4,4-diphenylbutan-2-yl)carbamate((R)-4''). To a solution of KOH (35 mg) in anhydrous DMSO (1.44 mL), diphenylacetonitrile (3) (0.669 g, 3.5 mmol, 1.25 equivalents) and a solution of tert-butyl(R)-2-methylaziridine-1-carboxylate((R)-2'') (0.4365 g, 2.8 mmol, 1.0 equivalent) in anhydrous DMSO (2.91 mL) were added. The reaction mixture was stirred at 90°C for 6 hours. 1Upon completion of the reaction, which was determined based on the consumption of (R)-2'' by 1H-NMR and TLC (Hex:EtOAc [8:2 ratio], using potassium permanganate staining, Rf = ca. 0.6), stirring was interrupted. The resulting mixture was then poured into 50 mL of water / brine 1:1, and DCM (50 mL) was added. The organic layer was separated, and the aqueous phase was further extracted with DCM (20 mL × 3). The combined organic layers were evaporated under reduced pressure, and the crude product was purified by column chromatography using DCM / ethyl acetate 98:2 as the eluent to give tert-butyl (R)-(4-cyano-4,4-diphenylbutan-2-yl)carbamate ((R)-4'') as a pale yellow solid (0.756 g, yield 78%). HRMS (ESI) m / z: [M+H] + C 22 H 26 Calculated for C21H23N2O2: 351.2067; Found: 351.2078. 1 1H NMR (400 MHz, CDCl3) δ 7.48 - 7.27 (m, 10H), 4.38 (s, 1H), 3.76 - 3.63 (m, 1H), 2.80 - 2.67 (m, 1H), 2.44 (dd, J = 14. , 5.2 Hz, 1H), 1.40 (s, 9H), 1.19 (d, J = 6.6 Hz, 3H) ppm, as shown in Figure 23.<…> 13 13C NMR (101 MHz, CDCl3) δ 154.69, 140.15, 140.05, 129.10, 129.06, 128.12, 127.08, 127.01, 122.53, 79.29, 49.37, 45.60, 44.48, 28.52, 22.27 ppm, as shown in Figure 24.

[0060] Step 2: Two-step / one-pot deprotection / reductive amination of tert-butyl (R)-(4-cyano-4,4-diphenylbutan-2-yl)carbamate ((R)-4'') to form (R)-methadone nitrile ((R)-5) To an ice-cold solution of tert-butyl(R)-(4-cyano-4,4-diphenylbutan-2-yl)carbamate((R)-4'') (0.200 g, 0.57 mmol, 1 equivalent) in DCM (2 mL), HCl (4 M dioxane solution, 2 mL, 14 mmol, 25 equivalents) was added dropwise under a nitrogen atmosphere, and the mixture was stirred at 0°C for 3 hours. Next, the solvent and residual HCl were removed under reduced pressure to obtain a slightly yellowish oily substance of Boc deprotected(R)-4'', which was redissolved in DMF (4.3 mL) and cooled in an ice bath. Formaldehyde (37% aqueous solution, 1.15 mL, 15 mmol, 25 equivalents) and NaCNBH3 (76 mg, 1.22 mmol, 2 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. Next, the solution was poured into 50 mL of saturated NaHCO3 and extracted with DCM (3 x 50 mL). The combined organic fraction was evaporated under reduced pressure, and the crude product was purified by column chromatography using CHCl3 / methanol 95:5 as the eluent to obtain (R)-4-(dimethylamino)-2,2-diphenylpentanenitrile ((R)-5) (138 mg, yield 87%). Chiral HPLC: one single enantiomer (ee>99%), as shown in Figure 25. HRMS (ESI) m / z: [M+H] + C 19 H 22 The calculated value of N2 is 279.1861; the measured value is 279.1924. 1 ¹H NMR (400 MHz, CDCl3) δ 7.48 - 7.24 (m, 10H), 2.68 (dd, J = 13.8, 6.5 Hz, 1H), 2.59 - 2.47 (m, 1H), 2.23 (dd, J = 13.9, 6.0 Hz, 1H), 2.13 (s, 6H), 0.91 (d, J = 6.6 Hz, 3H) ppm, as shown in Figure 26. 13 ¹³C NMR (10¹ MHz, CDCl₃) δ values: 141.34, 140.75, 128.85, 128.77, 127.89, 127.74, 127.46, 127.28, 122.93, 55.56, 49.70, 43.33, 40.02, 13.16 ppm, as shown in Figure 27.

[0061] Example 5: (S)-6-(dimethylamino)-4,4-diphenyl-3-heptanone hydrochloride ((S)-methadone*HCl) Example 5 describes a one-step method, shown in Figure 28, used to prepare (S)-6-(dimethylamino)-4,4-diphenyl-3-heptanone hydrochloride ((S)-methadone*HCl). This step was carried out in accordance with the procedure described in the literature (see WO2017 / 35224 and U.S. Patent Application Publication 2020 / 277250, which are incorporated herein by reference in their entirety, with some modifications.

[0062] (S)-4-(dimethylamino)-2,2-diphenylpentanenitrile ((S)-5) (6.62 g, 23.78 mmol, 1 equivalent) was added to a 200 mL two-necked round-bottom flask equipped with a thermocouple, magnetic stirring bar, and N2 inlet. The container was purged with N2 for 30 minutes, diluted with PhMe (66 mL, 10 volumes), and 3 M EtMgBr 2-MeTHF solution (12 mL, 35.68 mmol, 1.5 equivalents) was added dropwise over 30 minutes. The reaction mixture was then heated to 100°C using a heated mantle and stirred for 24 hours. When (S)-5 was consumed as determined by HPLC, the solution was cooled to 0°C and 2 M aqueous HCl solution (13 mL, 2 volumes) was added. The two-phase mixture was then heated to 50°C and vigorously stirred for 24 hours. The organic and aqueous fractions were separated, and the aqueous layer was cooled to 0°C in an ice bath. A seed crystal of (S)-methadone hydrochloride was added to a viscous solution to obtain a free-flowing slurry. The slurry was aged for 24 hours, cooled to 0°C, and the solid was collected by vacuum filtration. The slurry was dried under reduced pressure at 50°C for 24 hours to obtain (S)-6-(dimethylamino)-4,4-diphenyl-3-heptanone hydrochloride ((S)-methadone*HCl) as a white solid (5.20 g, yield 66%). HPLC purity: 99.6%. Chiral HPLC: one single enantiomer (ee>99%), as shown in Figure 29. HRMS (ESI) m / z: [M+H] + C 21 H 27 Calculated value of NO: 310.2165; Measured value: 310.2193. 1 1H NMR (400 MHz, DMSO) d6δ 10.60 (s, 1H), 7.48 - 7.24 (m, 10H), 3.10 (d, J = 13.9 Hz, 1H), 2.90 (p, J = 6.9 Hz, 1H), 2.63 (dd, J = 22.7, 4.7 Hz, 6H), 2.47 - 2.35 (m, 1H), 2.31 - 2.14 (m, 2H), 0.72 (t, J = 7.2 Hz, 3H), 0.48 (d, J = 6.5 Hz, 3H) ppm, as shown in Figure 30. 13 ¹¹C NMR (400 MHz, DMSO) d6 ) δ 210.64, 140.53, 140.07, 129.23, 129.06, 128.75, 128.53, 127.61, 64.57, 59.00, 38.78, 38.31, 38.05, 32.40, 14.72, 9.33 ppm, as shown in Figure 31.

[0063] Example 6: (R)-6-(dimethylamino)-4,4-diphenyl-3-heptanone hydrochloride ((R)-methadone*HCl) Example 6 describes a one-step method, shown in Figure 32, used to prepare (R)-6-(dimethylamino)-4,4-diphenyl-3-heptanone hydrochloride ((R)-methadone*HCl). This step was carried out in accordance with the procedure described in the literature (see WO2017 / 35224 and U.S. Patent Application Publication 2020 / 277250, which are incorporated herein by reference in their entirety, with some modifications.

[0064] (R)-4-(dimethylamino)-2,2-diphenylpentanenitrile ((R)-5) (2.80 g, 10.06 mmol, 1 equivalent) was added to a 100 mL two-necked round-bottom flask equipped with a thermocouple, magnetic stirring bar, and N2 inlet. The container was purged with N2 for 30 minutes, diluted with PhMe (28 mL, 10 volumes), and 3 M EtMgBr 2-MeTHF solution (5 mL, 15.09 mmol, 1.5 equivalents) was added dropwise over 30 minutes. The reaction mixture was then heated to 100°C using a heated mantle and stirred for 24 hours. When (R)-5 was consumed as determined by HPLC, the solution was cooled to 0°C and 2 M aqueous HCl (6 mL, 2 volumes) was added. The two-phase mixture was then heated to 50°C and vigorously stirred for 24 hours. The organic and aqueous fractions were separated, and the aqueous layer was cooled to 0°C in an ice bath. A seed crystal of (R)-methadone hydrochloride was added to a viscous solution to obtain a free-flowing slurry. The slurry was aged for 24 hours, cooled to 0°C, and the solid was collected by vacuum filtration. The slurry was dried under reduced pressure at 50°C for 24 hours to obtain (R)-6-(dimethylamino)-4,4-diphenyl-3-heptanone hydrochloride ((R)-methadone*HCl) as a white solid (2.44 g, yield 70%). HPLC purity: 99.5%. Chiral HPLC: one single enantiomer (ee>99%), as shown in Figure 33. HRMS (ESI) m / z: [M+H] + C 21 H 27 Calculated value of NO: 310.2165; Measured value: 310.2234. 1 1H NMR (400 MHz, DMSO) d6 δ 10.39 (s, 1H), 7.48 - 7.24 (m, 10H), 3.08 (d, J = 13.9 Hz, 1H), 2.91 (p, J = 7.0 Hz, 1H), 2.64 (dd, J = 21.5, 4.5 Hz, 6H), 2.48 - 2.36 (m, 1H), 2.29 - 2.13 (m, 2H), 0.73 (t, J = 7.2 Hz, 3H), 0.47 (d, J = 6.6 Hz, 3H) ppm, as shown in Figure 34. 13 ¹¹C NMR (400 MHz, DMSO) d6) δ 210.57, 140.58, 140.15, 129.28, 129.10, 128.76, 128.56, 127.63, 64.58, 58.83, 38.78, 38.02, 37.85, 32.38, 14.74, 9.38 ppm, as shown in Figure 35.

[0065] While the present invention has been disclosed with reference to details of preferred embodiments, it should be understood that this disclosure is intended to be illustrative rather than restrictive, as it is expected that modifications will readily come to mind for those skilled in the art within the spirit of the invention and within the scope of the amended claims.

Claims

1. A method for preparing (S)-methadone, (R)-methadone, or (R,S)-methadone from optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine, comprising: Ring-opening reaction of optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine with diphenylacetonitrile in the presence of a base to obtain ((S)- or (R)-) or racemic N-protected dinormesadone nitrile with preservation of stereochemistry; Two-step / one-pot deprotection / reductive amination of N-protected dinormethadone nitrile to obtain (R)-, (S)-, or (R,S)-methadone nitrile; and Reaction of (R)-, (S)-, or (R,S)-methadone nitrile with an organomagnesium halide reagent to form an ethyl-imine intermediate, followed by imine hydrolysis to obtain (R)-, (S)-, or (R,S)-methadone.

2. The method according to claim 1, wherein the organomagnesium halide reagent is EtMgX, where X is selected from Cl, Br, and I.

3. The N protecting group of N-protected 4-methylcyclic sulfamidate or N-protected 2-methylaziridine is fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), carboxybenzyl (Cbz), or acetyl (C(O)CH₂). 3 ), trifluoroacetyl (C(O)CF 3 ), benzyl (Bn), triphenylmethyl (CPh 3 The method according to claim 1, selected from ), and p-toluenesulfonyl (Ts).

4. The method according to claim 1, wherein the enantiomer excess (ee) exceeds a percentage selected from 90%, 95%, 97%, 99%, 99.5%, and 99.9%.

5. A method for preparing (S)-methadone hydrochloride, (R)-methadone hydrochloride, or (R,S)-methadone hydrochloride, comprising the following: Ring-opening reaction of optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine with diphenylacetonitrile in the presence of a base to obtain ((S)- or (R)-) or racemic N-protected dinormesadone nitrile with preservation of stereochemistry; Two-step / one-pot deprotection / reductive amination of N-protected dinormethadone nitrile to obtain (R)-, (S)-, or (R,S)-methadone nitrile; and Reaction of (R)-, (S)-, or (R,S)-methadone nitrile with an organomagnesium halide reagent to form an ethyl-imine intermediate, followed by hydrochloric acid-mediated imine hydrolysis to obtain (R)-, (S)-, or (R,S)-methadone hydrochloride.

6. The method according to claim 5, wherein the organomagnesium halide reagent is EtMgX, where X is selected from Cl, Br, and I.

7. The N protecting group of N-protected 4-methylcyclic sulfamidate or N-protected 2-methylaziridine is fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), carboxybenzyl (Cbz), or acetyl (C(O)CH₂). 3 ), trifluoroacetyl (C(O)CF 3 ), benzyl (Bn), triphenylmethyl (CPh 3 The method according to claim 5, selected from ), and p-toluenesulfonyl (Ts).

8. The method according to claim 5, wherein the enantiomer excess (ee) exceeds a percentage selected from 90%, 95%, 97%, 99%, 99.5%, and 99.9%.

9. The method according to claim 1 or 5, comprising a method for preparing an N-protected 4-methyl-cyclic sulfamidate selected from benzyl(S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide, benzyl(R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide, and benzyl(R,S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide.

10. A method for preparing (R)-, (S)-, or (R,S)-methadone nitrile, comprising the following: Ring-opening reaction of optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine with diphenylacetonitrile in the presence of a base to obtain ((S)- or (R)-) or racemic N-protected dinormesadone nitrile with preservation of stereochemistry; Two-step / one-pot deprotection / reductive amination of N-protected dinormethadone nitrile to obtain (R)-, (S)-, or (R,S)-methadone nitrile.

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